A retrovirus designated human immunodeficiency virus (HIV), particularly the strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus, is the etiological agent of the complex disease that includes progressive destruction of the immune system (acquired immune deficiency syndrome; AIDS) and degeneration of the central and peripheral nervous system. A common feature of retrovirus replication is the insertion by virally-encoded integrase of +proviral DNA into the host cell genome, a required step in HIV replication in human T-lymphoid and monocytoid cells. Integration is believed to be mediated by integrase in three steps: assembly of a stable nucleoprotein complex with viral DNA sequences; cleavage of two nucleotides from the 3′ termini of the linear proviral DNA; covalent joining of the recessed 3′ OH termini of the proviral DNA at a staggered cut made at the host target site. The fourth step in the process, repair synthesis of the resultant gap, may be accomplished by cellular enzymes.
The HIV genome is made up of single-stranded RNA which comprises several genes that code for structural proteins common to all retroviruses and additional genes that code for accessory proteins specific to HIV (A. D. Frankel and J. A. T. Young, Annu. Rev. Biochem. 67:1-25 (1998)). Open reading frames encoding structural proteins include the pol gene (Ratner et al., Nature 313: 277-284 (1985)), which encodes reverse transcriptase, integrase and HIV protease, the gag gene, which encodes the core proteins of the virion (Toh et al., EMBO J. 4: 1267-1272 (1985); Power et al., Science 231: 1567-72 (1986); Pearl et al., Nature 329: 351-54 (1987)), and the env gene, which encodes gp120 (surface) and gp41 (TM/transmembrane). All three enzymes encoded by the pol gene have been shown to be essential for the replication of HIV.
It is known that some antiviral compounds which act as inhibitors of HIV replication are effective agents in the treatment of AIDS and similar diseases, including reverse transcriptase inhibitors such as azidothymidine (AZT) and efavirenz and protease inhibitors such as indinavir and nelfinavir and integrase inhibitors such as raltegravir.
Examples of references that are related to HIV integrase inhibitors include the following:    Kinzel et al., Tet. Letters 2007, 48(37): 6552-6555; Ferrara et al., Tet. Letters 2007, 48(37): 8379-8382; and Muraglia et al., J. Med. Chem. 2008, 51: 861-874;    International Patent Appln. Publication Nos. WO 11/045330, WO2006/121831, WO 2006/103399, WO 11/121105, WO2005/87766, WO 2010/042391, WO 2010/042392, WO 06/116764, and WO 2008/48538;    US Patent Appln. Publication Nos. 2004/229909, 2007/0083045, 2007/0142635, 2007/0111984, 2005/0054645, 2006/0276466, 2007/0049606, 2007/0111985, 2007/0112190, 2007/0281917, 2008/0004265, 2007/0149556, and 2007/0123524; and    U.S. Pat. No. 7,232,819, U.S. Pat. No. 7,169,780, U.S. Pat. No. 7,217,713, U.S. Pat. No. 7,279,487, U.S. Pat. No. 7,135,467, U.S. Pat. No. 7,037,908, U.S. Pat. No. 7,211,572, U.S. Pat. No. 7,414,045, U.S. Pat. No. 7,115,601, U.S. Pat. No. 7,157,447, U.S. Pat. No. 7,173,022, U.S. Pat. No. 7,176,196, U.S. Pat. No. 7,192,948, U.S. Pat. No. 7,273,859, and U.S. Pat. No. 7,419,969.